| Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects -> Monitor Keywords |
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  Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defectsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Animal Or Plant CellThe Patent Description & Claims data below is from USPTO Patent Application 20070202084. Brief Patent Description - Full Patent Description - Patent Application Claims
INCORPORATION BY REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Nos. 60/751,237; 60/751,381; and 60/751,414, all of which were filed Dec. 14, 2005. The entire teachings of the above-mentioned applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Articular cartilage is an elastic tissue that covers the ends of bones in joints and enables the bones to move smoothly. The repair of damaged articular cartilage represents one of the most challenging problems in orthopedics today. When articular cartilage is damaged, it does not heal as rapidly or effectively as other tissues in the body. Rather, the damage tends to spread and the bones may rub directly against each other, which results in pain, reduced mobility and loss of joint function. [0003] Various therapeutic approaches to stimulate regeneration of articular cartilage and subchondral bone have been developed with varying degrees of success. Examples of such therapeutic approaches include osteochondral grafting and autologous chondrocyte implantation. However, there is still a need to develop methods for treating articular cartilage defects, such as osteochondral and chondral defects. SUMMARY OF THE INVENTION [0004] The present invention generally is directed to a method for treating an osteochondral defect or a chondral defect in a subject by the use of a composite that includes a hyaluronic acid derivative and at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor. [0005] In one embodiment, the invention is directed to a method for treating an osteochondral defect or a chondral defect in a subject. The method includes implanting a composite at a site of the osteochondral or chondral defect. The composite includes a hyaluronic acid derivative; and at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor. The cell, cellular growth factor or cellular differentiation factor is impregnated in, or coupled to, the hyaluronic acid derivative. The hyaluronic acid derivative includes carboxyl functionalities that are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. [0006] In another embodiment, the invention is directed to a method for regenerating or promoting regeneration of cartilage and/or bone in an osteochondral defect or a chondral defect in a subject. The method includes forming a scaffold that includes a hyaluronic acid derivative and a support, wherein a portion of carboxyl functionalities of the hyaluronic acid derivative is derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. The method also includes the steps of impregnating in, or coupling to, the scaffold at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor; and implanting the scaffold impregnated or coupled with at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor at a site of the osteochondral defect or chondral defect, thereby providing a mechanism for the delivery of the cell, cellular growth factor or cellular differentiation factor to the site of the osteochondral or chondral defect to regenerate or promote regeneration of cartilage and bone in the osteochondral defect or chondral defect. [0007] The natural repair of osteochondral or chondral defects can be enhanced with a proper matrix that provides structural support and molecular cuing to stimulate repair. For example, in the current invention, subject's own cells, such as healthy cartilage cells or mesenchymal stem cells, can be harvested and impregnated in, or coupled to, the hyaluronic acid derivative or the hyaluronic acid derivative and one or more biocompatible, biodegradable supports. The hyaluronic acid derivative optionally together with the biocompatible support can provide structural support and molecular cuing for the impregnated or coupled cells to migrate, multiply and stimulate regeneration of cartilage. Likewise, the cellular growth and differentiation factors can be loaded into the matrix and provide additional molecular cuing for the cells to produce cartilage or bone tissue, or provide signals for the cells to differentiate down the chondrogenic or osteogenic lineage. The biocompatible, biodegradable support and/or hyaluronic acid derivative will be absorbed by the body while the cartilage tissue regeneration takes place. Thus, there is no need to remove the support and hyaluronic acid derivative from the subject after the regenerated articular cartilage restores its function, leaving no artificial materials at the treatment site. BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIGS. 1A and 1B are scanning electron microscopy (SEM) images of a composite of the invention, including a freeze-dried crosslinked hyaluronic acid (HA) sponges, at two different magnifications. [0009] FIGS. 2A and 2B are scanning electron microscopy (SEM) images of a composite of the invention, including a freeze-dried crosslinked hyaluronic acid (HA) sponges, at two different magnifications. [0010] FIG. 3 is a cross sectional view of the composite of FIGS. 2A-2B, showing interconnected structural support that can provide cues for ingrowth of cells, cellular growth factors or cellular differentiation factors for treating an osteochondral or chondral defect. DETAILED DESCRIPTION OF THE INVENTION [0011] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. [0012] As used herein, the term "hyaluronic acid derivative" means hyaluronic acid derivatized in that carboxyl functionalities of the hyaluronic acid (HA) (a portion or all) are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. As used herein, hyaluronic acid, and any of its salts which are often referred to as "hyaluronan" (e.g., sodium, potassium, magnesium, calcium or ammonium salts) are represented by the term "HA." Typically, HA comprises disaccharide units of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc), which are alternately linked, forming a linear polymer. [0013] N-acylurea and O-acyl isourea derivatives for the invention are as shown in the bracketed fragments in the following structural formulas (I) and (II): [0014] In structural formulas (I) and (II), each R.sub.1 can be the same or different. Each R.sub.1 is selected from the group consisting of hydrogen; substituted or unsubstituted hydrocarbyl groups (linear or branched, or cyclic or acyclic) optionally interrupted by one or more heteroatoms; substituted or unsubstituted alkoxy; substituted or unsubstituted aryloxy; and substituted or unsubstituted aralkyloxy. Examples of substituted or unsubstituted hydrocarbyl groups (linear or branched, or cyclic or acyclic) optionally interrupted by one or more heteroatoms include optionally substituted aliphatic groups (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl and cycloaliphaticalkyl); optionally substituted aryl groups (including heteroaryl groups); optionally substituted aliphatic groups interrupted by one or more heteroatoms (e.g., heterocyclyl, cycloaliphaticalkyl and heterocyclylalkyl); and optionally substituted, partially aromatic and partially aliphatic groups (e.g., aralkyl and heteroaralkyl). Suitable optional substituents are those that do not substantially interfere with the properties of the resulting crosslinked HA composition. Suitable substituents for carbon atoms of hydrocarbyl groups include --OH, halogens (--Br, --Cl, --I, --F), --OR.sup.a, --O--COR.sup.a, --COR.sup.a, --CN, --NCS, --NO.sub.2, --COOH, --SO.sub.3H, --NH.sub.2, --NHR.sup.a, --N(R.sup.aR.sup.b), --COOR.sup.a, --CHO, --CONH.sub.2, --CONHR.sup.a, --CON(R.sup.aR.sup.b), --NHCOR.sup.a, --NR.sup.bCOR.sup.a, --NHCONH.sub.2, --NHCONR.sup.aH, --NHCON(R.sup.aR.sup.b), --NR.sup.bCONH.sub.2, --NR.sup.bCONR.sup.aH, --NR.sup.cCON(R.sup.aR.sup.b), --C(.dbd.NH)--NH.sub.2, --C(.dbd.NH)--NHR.sup.a, --C(.dbd.NH)--N(R.sup.aR.sup.b), --C(.dbd.NR.sup.c)--NH.sub.2, --C(.dbd.NR.sup.c)--NHR.sup.a, --C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NH--C(.dbd.NH)--NH.sub.2, --NH--C(.dbd.NH)--NHR.sup.a, --NH--C(.dbd.NH)--N(R.sup.aR.sup.b), --NH--C(.dbd.NR.sup.c)--NH.sub.2, --NH--C(.dbd.NR.sup.c)--NHR.sup.a, --NH--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NR.sup.dH--C(.dbd.NH)--NH.sub.2, --NR.sup.d--C(.dbd.NH)--N(R.sup.aR.sup.b), --NR.sup.d--C(.dbd.NR.sup.c)--NH.sub.2, --NR.sup.d--C(.dbd.NR.sup.c)--NHR.sup.a, --NR.sup.d--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NHNH.sub.2, --NHNHR.sup.a, --NHR.sup.aR.sup.b, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.a, --SO.sub.2NR.sup.aR.sup.b, --SH, --SR.sup.a, --S(O)R.sup.a, and --S(O).sub.2R.sup.a. In addition, an alkyl, alkylene, alkenyl or alkenylene group can be substituted with substituted or unsubstituted aryl group to form, for example, an aralkyl group such as benzyl. Similarly, aryl groups can be substituted with a substituted or unsubstituted alkyl or alkenyl group. [0015] R.sup.a-R.sup.d are each independently an alkyl group, aryl group, including heteroaryl group, non-aromatic heterocyclic group or --N(R.sup.aR.sup.b), taken together, form a substituted or unsubstituted non-aromatic heterocyclic group. The alkyl, aromatic and non-aromatic heterocyclic group represented by R.sup.a-R.sup.d and the non-aromatic heterocyclic group represented by --N(R.sup.aR.sup.b) can optionally be substituted. [0016] In other embodiments, R.sub.1 is an optionally substituted aliphatic group (cyclic or acyclic, or linear or branched). More preferably, R.sub.1 is an alkyl group, such as C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, 2-propyl, tert-butyl, and the like). Preferably, each R.sub.1 is ethyl. [0017] Each R.sub.2 is independently a substituted or unsubstituted linking group including one or more of hydrocarbylene groups (cyclic or acyclic, or linear or branched) optionally interrupted by one or more heteroatoms. Examples include optionally substituted aliphatic groups (e.g., alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene and cycloaliphaticalkylene); optionally substituted arylene (including heteroaryl groups); optionally substituted aliphatic groups interrupted by one or more heteroatoms (e.g., heterocyclylene, cycloaliphaticalkylene and heterocyclylalkylene); and optionally substituted, partially aromatic and partially aliphatic groups (e.g., aralkylene and heteroaralkylene). Suitable optional substituents are as those described above for R.sub.1. [0018] In some embodiments, R.sub.2 includes or is interrupted by other groups, e.g, carbonyl, amide, oxy, sulfide, disulfide, and the like. In other embodiments, R.sub.2 is a cycloaliphatic, arylene, heteroarylene, or heterocyclylene group. In still other embodiments, R.sub.2 is 1,6-hexamethylene, octamethylene, decamethylene, dodecamethylene, PEG, --CH.sub.2CH.sub.2--S--S--CH.sub.2CH.sub.2-, para-phenylene-S--S-para-phenylene, meta-phenylene-S--S-meta-phenylene, ortho-phenylene-S--S-ortho-phenylene, ortho-phenylene, meta-phenylene or para-phenylene. More preferably, R.sub.2 is phenylene. Preferably, R.sub.2 is para-phenylene. [0019] In one embodiment, the wavy line connected to R.sub.2 in structural formulas (I) and (II) represents hydrogen, substituted or unsubstituted hydrocarbyl groups (linear or branched, or cyclic or acyclic) optionally interrupted by one or more heteroatoms; alkoxy; aryloxy; or aralkyloxy, as described for R.sub.1. In another embodiment, the wavy line connected to R.sub.2 in structural formulas (I) and (II) represents optionally substituted N-acyl urea group or O-acyl isourea group, as shown below in structural formulas VI-VIII. Continue reading... Full patent description for Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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